HIV infection remains a major medical problem. Currently available HIV drugs include nucleoside reverse transcriptase (RT) inhibitors, non-nucleoside reverse transcriptase inhibitors as well as peptidomimetic protease inhibitors. Each of these drugs can only transiently restrain viral replication if used alone. Insufficient drug potency, non-compliance, restricted tissue penetration and drug-specific limitations within certain cell types may account for the incomplete suppression of sensitive viruses.
Furthermore, HIV is an extremely heterogeneous virus. The clinical significance of this heterogeneity is evidenced by the ability of the virus to evade immunological pressure, survive drug selective pressure, and adapt to a variety of cell types and growth conditions. Therefore, diversity is a major obstacle to pharmacologic or immunologic control of human immunodeficiency virus infection.
One of the critical pathways in a retroviral life cycle is the processing of polyprotein precursors by aspartic protease. For instance with the HIV virus the gag-pol protein is processed by HIV protease. The correct processing of the precursor polyproteins by the aspartic protease is required for the assembly of infectious virions, thus making the aspartic protease an attractive target for antiviral therapy. In particular for HIV treatment, the HIV protease is an attractive target.
HIV protease inhibitors (PIs) are commonly administered to AIDS patients in combination with other anti-HIV compounds such as, for instance nucleoside reverse transcriptase inhibitors (NRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs), nucleotide reverse transcriptase inhibitors (NtRTIs) or other protease inhibitors. Despite the fact that these antiretrovirals are very useful, they have a common limitation, namely, the targeted enzymes in the HIV virus are able to mutate in such a way that the known drugs become less effective, or even ineffective against these mutant HIV viruses. Or, in other words, the HIV virus creates an ever increasing resistance against the available drugs.
In search of compounds that are able to meet the medical need in HIV treatment, sulfonamide derivatives of general formula (A) have been prepared and are found to have a broad virological spectrum with little variance in fold resistance, i.e. difference in viral inhibitory activity on HIV wild-type and HIV mutant strains (WO 2004003817, WO 2003106461, WO 2003097616, WO 2003090691, WO 2003090690, WO 2003078438, WO 2003076413, WO 2003070976, WO 2003064406, WO 2003057173, WO 2003053435, WO 2003049746, EP 1265073, WO 2002092595, WO 2002083657, WO 2002081478, WO 2001025240, WO 9967417, WO 9967254, Ohtaka et al. Protein Science (2002), 11(8), 1908-1916, Gatanaga et al. Journal of Biological Chemistry (2002), 277(8), 952-5961, Ghosh et al. Antiviral Research (2002), 54(1), 29-36, Yoshimura et al. Journal of Virology (2002), 76(3), 1349-1358, Ghosh et al. Farmaco (2001), 56(1-2), 29-32, Ghosh et al. Bioorganic & Medicinal Chemistry Letters (1998), 8(6), 687-690)

Despite the obtained results in the art, there is a continuous need for improved HIV protease inhibitors. Such improved HIV protease inhibitors can only be made if the knowledge on the medicinal chemistry allows the preparation of chemical variants. Compounds of general formula (A) are prepared in the art via a coupling reaction using hexahydro-furo[2,3-b]furan-3-ol as an intermediate. Further exploration of the hexahydro-furo[2,3-b]furan pharmacophore as a scaffold for new and improved HIV protease inhibitors has been prevented thus far because of a lack of knowledge on how to prepare substituted variants of hexahydro-furo[2,3-b]furan-3-ol.